Anticancer Applications of Nanostructured Silica-Based Materials Functionalized with Titanocene Derivatives: Induction of Cell Death Mechanism through TNFR1 Modulation
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AuthorGómez-Ruiz, Santiago; García-Peñas, Alberto; Prashar, Sanjiv; Rodríguez-Diéguez, Antonio; Fischer-Fodor, Eva
Nanostructured silicaTitanoceneCytotoxicityAnticancerTumor necrosis factorTNFR1 modulation
Gómez-Ruiz, Santiago; et. al. Anticancer Applications of Nanostructured Silica-Based Materials Functionalized with Titanocene Derivatives: Induction of Cell Death Mechanism through TNFR1 Modulation. Materials 2018, 11, 224 [http://hdl.handle.net/10481/51305]
SponsorshipWe gratefully acknowledge financial support from FEDER and the Ministerio de Economía y Competitividad, Spain (grant no. CTQ2015-66164-R) and the Romanian UEFISCDI Exploratory Research Project PN-III-P4-ID-PCE-2016-0870, IMPRESS.We would also like to thank Universidad Rey Juan Carlos and Banco de Santander for supporting our Research Group of Excellence QUINANOAP. Finally, we thank D. Pérez for valuable discussion and S. Carralero and C. Forcé for their assistance with solid-state NMR experiments.
A series of cytotoxic titanocene derivatives have been immobilized onto nanostructured silica-based materials using two different synthetic routes, namely, (i) a simple grafting protocol via protonolysis of the Ti-Cl bond; and (ii) a tethering method by elimination of ethanol using triethoxysilyl moieties of thiolato ligands attached to titanium. The resulting nanostructured systems have been characterized by different techniques such as XRD, XRF, DR-UV, BET, SEM, and TEM, observing the incorporation of the titanocene derivatives onto the nanostructured silica and slight changes in the textural features of the materials after functionalization with the metallodrugs. A complete biological study has been carried out using the synthesized materials exhibiting moderate cytotoxicity in vitro against three human hepatic carcinoma (HepG2, SK-Hep-1, Hep3B) and three human colon carcinomas (DLD-1, HT-29, COLO320) and very low cytotoxicity against normal cell lines. In addition, the cells' metabolic activity was modified by a 24-h exposure in a dose-dependent manner. Despite not having a significant effect on TNFα or the proinflammatory interleukin 1α secretion, the materials strongly modulated tumor necrosis factor (TNF) signaling, even at sub-cytotoxic concentrations. This is achieved mainly by upregulation of the TNFR1 receptor production, something which has not previously been observed for these systems.